Category: Low Dose Medicines

  • THE COLLAGEN MEDICAL DEVICES IN THE LOCAL TREATMENT OF THE ALGIC ARTHRO-RHEUMOPATHIES

    REVIEW OF THE CLINICAL STUDIES AND CLINICAL ASSESSMENTS 2010-2012

    INTRODUCTION

    Reliable epidemiologic data recorded in Italy (Mannaioni et Al., 2003) and in Europe [Jordan et Al., 2003-European League Against Rheumatism (EULAR)] show that 15-20% of the general population suffers from pathologies involving the osteo-arthro-myo-fascial Apparatus (better defined as arthro-rheumopathies), representing 70% of the patients with chronic pain.


    – In the near future, these data will probably undergo an increase, especially due to increased life expectancy, overall average increase in body weight, greater propensity to inactivity amid people above 50, higher incidence of amateur sports activity and consequent traumas (mostly among people aged between 20 and 45), overuse of NSAIDs and unhealthy diet, basically high in proteins. The arthro-rheumopathies (connective tissue inflammatory and/or degenerative diseases) are all characterized by collagen disorders.

    Collagen’s physiological tissue organization and quantitative and qualitative composition – which dramatically decrease from = 60 years of age (Heine, 2009) – determines the organoleptic characteristics of connective tissues. – Collagens are merged into a vast family of structural proteins of the extra-cellular matrix having unique and peculiar characteristics, also from the phylogenetic point of view (in Milani, 2010).

    Up to the present more than 30 genetically
    distinct varieties (Types) of collagen have been identified.Genetic alterations of some Types of
    collagen determine complex and paradigmatic phenotypes (alterations in the collagen Type I: e.g. osteogenesis imperfecta; Type I, III, V: e.g. Ehlers-
    Danlos syndrome; Type IV: e.g. Alport syndrome; Type II, XI: e.g. cartilage genetic diseases). The fibrillar collagen Type I (COL1A1 and COL1A2 coding genes) is the most abundant ubiquitous protein in adult humans, accounting for 90%of the total collagen: it is involved in the

    A

    A – Continuity of collagen fibers in the ligament of adult rats.
    Electron Microscope images from Provenzano P.P. and Vanderby R. Jr. – Collagen fibril morphology
    and organization: Implication for force transmission in ligament and tendon. Matrix
    Biology 25(2006) 71-84.

    composition of the main connective tissues and represents the bulk of certain structures such as skin, dentine, cornea, joint capsules, ligaments, tendons, aponeurotic layers and fibrous membranes. – In the tendons, for example, collagen Type I = 97%; elastin = 2%; proteoglycans = 1-5%; inorganic components (Cu, Mn, Ca) = 0.2% (Jozsa and Kannaus, 1997; Lin et Al., 2004); in ligaments, collagen Type I = 85% (Frank, 2004; Vereeke et Al., 2005). The in vivo fibrillogenesis is a multi-step process involving both the intracellular compartment and the extracellular one, defined by tenocyte (a very specialized fibrocyte) (FIG. 1). – The tenocyte, in addition to collagen Type I, also synthesizes the matrix proteoglycans (PGs) and the metalloproteinase (MMP) 1-interstitial which is involved, together with the MMP8-neutrophil, in the degradation of the fibrils, either because old or damaged by the inflammatory/traumatic process (Birk et Al., 1995; Canty, 2004). The MMP1 is primarily involved in the processes of fibrillo- (collagen)-lysis: the study of Maeda et Al. (1995) highlights a very high concentration of MMP1 in the synovial fluid of patients with rheumatoid arthritis, which is related to the degree of inflammation (reliable marker of the disease status). Provenzano andVanderby Jr. (2006) ), using the electron microscope, exhibit a wide range of very impressive photographs proving that healthy adults collagen fibrils (FIG. 2A) are very precise, parallel to each other, continuous and laid longitudinally along the main axes of the anatomical structures to which they belong and which characterize, transmitting the force directly and not through the PGs bridges.

    – The collagen turnover is very slow. The mechanical failure and the presence of free radicals can increase the degenerative process, causing a spontaneous, slow and imperfect neofibrillogenesis: the process of spontaneous repair leads to the neoformation of disordered, twisted, juxtaposed, discontinuous fibers, (FIG. 2B), morphologically much more similar to the fetal ones rather than the adult ones (Provenzano et Al., 2001). It also leads to increased vascularization and increased deposits and clusters of inflammatory cells. These phenomena all contribute to the further weakening of collagen Type I (Shrive et Al., 1995; Frank et Al., 1999) and to the increased synthesis of collagen Type III (Liu et Al., 1995; Hsu et Al., 2010), which is functionally much less suitable.
    B

    B – Post-traumatic repair of the collagen texture.
    Electron Microscope images from Provenzano P.P., Hurschler C., Vanderby R. Jr. – Connect.
    Tiss. Res. 42:123-133, 2001.

    During the fibrillogenesis process, the PGs play a crucial role in guiding and stabilizing neofibrils, assisted by the SLPR (Small Leucine Rich Proteoglycans) (Jepsen et Al., 2002), represented above all by decorin, lumican, and fibromodulin. The rare overt genetic alterations of these 3 small PGs affect distinct phenotypes, clinically severe. – Minor alterations with variable penetrance and expressivity are probably not diagnosed and are the primary cause of highly pathologically susceptible conditions: collagen fibrils altered in shape and diameter which affect the joints and posture long before the physiological decay. – I conclude these brief topics on collagen, which supplement and detail what presented in a previous publication (Milani, 2010) to which I refer, indicating that collagen is also a template for bone mineralization, which promises new and revolutionary solutions in Orthopedics and Traumatology.

    The anatomical structures composing the extra-articular environment of the joints – with containing and stabilizing functions – are represented by:

    1. joint capsule, ligaments and fibrous membranes (“direct hold”);
    2. tendons and muscles (“indirect hold”).

    These elements – which unite and wrap the distal end of a bone and the proximal end of the adjacent bone (superoinferior) (bone segments in connection) – are the actors of the containment-stabilization and of the joint mobility.
    – Although anatomically distinct and functionally different, these structures are in close continuity (contiguous or overlapping anatomical planes; some collagen fibers of each structure merge with the neighboring ones) to form an elastic-stretch sleeve performing primarily two functions:

    1. Articular establishment in static / dynamic physiological position;
    2. Articular mobility with maximum range.

    FIGURE 3 shows as exemplification the fibrous structures of the extra-articular environment of the elbow.
    – In addition to the extra-articular structures, few joints also have intra-articular intrinsic ligaments that connect two skeletal segments inside the joint capsule (e.g. cruciate ligaments of the knee joint, coxofemoral round ligament).
    – The extra-articular structures (primarily: joint capsule, ligaments and tendons) are constituted by collagen Type I: the quality and the quantity of this protein ensure a physiological joint movement, repeated over time and optimal movement.

    Progressive depletion and / or damage to organoleptically suitable collagen Type I is produced by aging (discrepancy between neofibrillogenesis and fibrillo-lysis), misuse or disuse of the joints, traumas aggravated by the coexistence of internal diseases and – in some age groups – even by vitamin deficiencies (vitamin C, but also vitamin A and E), copper
    deficiency, noble proteins deficiency, and the use / abuse of drugs (particularly corticosteroids).
    – In particular, Elder et Al. (2001), Warden (2005), and Warden et Al. (2006) show that NSAIDs COX-2 inhibitors inhibit the healing of injured ligaments, leading to the lack of mechanical strength (imbalance between joint stability and mobility) and causing extra- and intra-articular damages. The trial of these drugs demonstrates unequivocally that the anti-inflammatory benefit in the short term is converted into serious harm in the medium and long term.
    – Fournier et Al. (2008), and Ziltener et Al. (2010) maintain that the use of NSAIDs in the treatment of periarticular soft tissues (ligaments, capsule) should be very limited in time, or absent.

    A – Left elbow joint, front.
    B – Right elbow joint, front.
    The containing and stabilizing
    structures of the elbow joint are
    represented by extra-articular
    connective-collagen Type 1 structures.
    They are represented by:
    – ulnar collateral ligament (A, B);
    – radial collateral ligament (A, B);
    – anular radial ligament (A, B);
    – sacciform recess (A);
    – joint capsule (lifted in A; B);
    – brachial biceps tendon (B).
    All these structures allow the
    large variations in flexion, extension
    and torsion of the forearm on
    the arm.
    – Images translated and elaborated by the
    author from W. Spalteholz – R. Spanner,
    Atlante di Anatomia Umana. Società
    Editrice Libraria (Vallardi) – Milano, 5th Italian
    edition (1962) in the 16th German edition
    (1959-61); 1st Vol.; pp. 232-3.

    Barton and Bird (1996) indicate the laxity or hyperlaxity of anatomical structures as the most important cause of pain of one or more joints. The quoted authors’ studies follow those by:

    • Rotes-Querol (1957), which identified joint laxity as the main factor of altered posture;
    • Teneff (1960), indicating the clinical significance of congenital
      joint laxity;
    • Donayre and Huanaco (1966), which show that the orthopedic
      joint laxity is the cause of many diseases (defined
      by the authors as “arthrocalasis”).
      Recently:
    • Philippon and Schenker (2005) show high incidence of
      coxofemoral traumas in athletes with femoral laxity;
    • Paschkewitz et Al. (2006) describe the generalized ligament
      laxity associated with proximal dislocation of the tibio-
      peroneal joint;
    • Hauser and Dolan (2011), indicate in joint instability and
      unhealed ligament injuries the primary cause of osteoarthritis.

    These are just some historical data and the most recent ones among those that can be extrapolated from the available literature on the topic which indicate that the joint hypermobility due to deficiency of joint containment (ultimately: deficiency of collagen Type I in the extra-articular environment) is the primary cause of the arthropatic etiology.
    It is necessary to distinguish between joint hypermobility due to impaired containment from the one due to paraphysiological laxity, such as:

    • in childhood (Cheng et Al., 1993; Bird, 2005; Simpson, 2006);
    • in females, especially during the menstrual cycle (Schultz, 2005);
    • In individuals belonging to African (Beighton et Al., 1973) and eastern (Walker, 1975) anthropological varieties,

    and the one due to joint instability of various pathological degree, which starts when the contiguous bone segments forming a joint do not respect the optimal axes and – consequently the angles among them. Paradigmatic examples – not the only ones, though – of such situations are:

    • valgus/varus tibio-femoral joint (FIG. 4) and valgus/varus coxofemoral joint,
    • the extra/internal rotation of the head of the femur in the acetabulum,
    • the lordosis/kyphosis of the rachis segments,
    • cavus/flat foot.

    Situations that can worsen joint hypermobility are paraphysiological variations and real alterations of the diaphyseal shape, the alteration of the muscle tone and abnormal proprioception.

    All the above conditions necessarily lead to pathological osteo-cartilaginous hyperload which cause the overuse processes. The bone reacts with the production of marginal osteophytes, subchondral bone cysts, subcortical hardenings or deformities and/or epiphyseal osteopenia.

    These extra-physiological forces cause, especially in the load joints, slippage of the adjacent bone heads, which are anteroposterior, medium-lateral and rotational of greater or lesser severity.

    – In such situations the loose structures of the extra-articular environment are exposed to mechanical stress: the pain due to extra-articular cause is added to the one due to intra-articular cause (which is frequently inflammatory), thus aggravating the status and prognosis of the disease.

    The organism performs mechanisms of local and remote compensation by establishing the activation (hyperactivation) of ascendants and descendants muscle-proprioceptive chains which only rarely get the desirable effect: the control of the vascular tone is unintentional and self-organizing, at central and peripheral level.

    – Currently, the treatment of arthro-reumopaties offers different options; it includes different, unique treatments or – more frequently – a combination of:

    • non-pharmacological treatments (e.g. ultrasound therapy, magnetic therapy, laser therapy, TENS, acupuncture, moxibustion, etc.);
    • conventional pharmacological treatments [e.g. COXIB, NSAIDs, paracetamol, corticocosteroids (the latter also intra- articularly injected)];
    • unconventional pharmacological treatments [e.g. specific medicines formulated by Homeopathy, Homotoxicology (the latter also via intra-articular injection, periarticular injection, mesotherapy, homosiniatry treatment), Physiological Regulating Medicine, Herbal Medicine];
    • physical-rehabilitation treatments (see review by Di Domenica et Al., 2004);
    • surgical treatment: mobile (prosthesis, especially hip, knee, shoulder) or fixed (arthrodesis).

    Symptomatic slow-acting treatments include viscosupplementation with hyaluronic acid (see review by Bellamy et Al., 2008) or with hylan G-F 20 (derived from the hyaluronic acid) (see review by Conrozier and Chevalier, 2008), administered mainly via injection into the knee, hip and shoulder. They are viscous lubricants whose prevailing action is supplementary and cushioning.

    The viscosupplementation replaces the (usually degraded) hyaluronic acid of the synovial fluid of the joints of the pa- tients affected by osteoarthritis.

    The hyaluronic acid is mostly used to inject the knee in or- der to treat gonarthrosis.

    Nevertheless, the members of the EULAR (European League Against Rheumatism) Committee for clinical trials on osteoarthritis of the knee met in 1998 and came to the con- clusions that the hyaluronic acid and symptomatic slow-ac- ting antiarthritic drugs have modest efficacy in gonarthro- sis. Moreover, they stated that the patients who may benefit from this therapy are hardly identifiable and that pharma- coeconomic data are uncertain. The opinion of 21 experts has placed the use of the hyaluronic acid for the treatment of gonarthrosis in 13th place out of 23 entries (Pendleton et Al., 2000).

    • Since 2010, also the treatment of algic/degenerative dis- eases of the musculoskeletal system takes advantage of the

    use of the injectable Collagen* Medical Devices (MDs) (Gu- na Laboratories, Milan – Italy).

    The Collagen MDs can be used alone (e.g. MD-Lumbar: low back pain with high arthritic imprint), or – more frequently variously mixed according to the patient’s clinical and func- tional needs (e.g. MD-Lumbar + MD-Neural: low back pain with algic nerve imprint; MD-Lumbar + MD-Muscle: low back pain with prevailing myo-fascial imprint).

    The Collagen MDs are applied locally through:

    1. periarticular injections
    2. intra-articular injections (obviously in the joints allo- wing a clear intra-articular approach: knee, hip, shoul- der)
    3. subcutaneous and/or intradermal injections (in trig- ger points, in spontaneously painful points, in points whe- re average digitopressure causes pain, in local acupunc- ture points, etc.).

    or systemically:

    – intramuscular injections (into muscle trigger points), and in supportive treatment (mainly at home).

    The 13 Collagen Medical Devices are produced from der- mal tissue of swine origin (trophism) + ancillary excipients of natural origin allowing an efficient and specific positio- ning on site (tropism).

    The ancillaries were selected according to different criteria such as: traditional use, dedicated literature, clinical eviden- ce, quality profiles, etc.

    The swine’s dermal tissue contains » 50% of collagen Type I (Gly = 22.8%; Pro = 13.8%; OH-Pro = 13%).

    • The purpose of the in situ injections of the Collagen MDs is essentially structural.

    From 2010 to 2012 10 clinical trials on humans were car- ried out, involving most of the treatable anatomical districts with Collagen MDs: 3 gonarthrosis, 1 patello-femoral arth- ropathy, 2 coxarthrosis, 2 shoulder pain, 1 PMID (Painful Mi- nor Intervertebral Dysfunctions) of cervical rachis, 1 acute lumbar back pain.

    • In the following pages it is presented the synopsis of the experiments; the Authors’ conclusions of the 10 trials are faithfully reported.

    ►     EFFICACY AND SAFETY OF THE GUNA MDs INJEC- TIONS IN THE TREATMENT OF OSTEOARTHRITIS OF THE KNEE

    Authors: Rashkov R., Nestorova R., Reshkova V.

    • Clinical Assessment presented at the Bulgarian National Congress of Rheumatology – Pravets (October 2011), at the European Congress on Osteoporosis and Osteoarthritis – Bor- deaux (F) (March 2012), and at the 3rd Bulgarian National Congress on Osteoporosis and Osteoarthritis – Sandanski (No- vember 2012).

    Experimental sites: Rheumatology Clinic of the Medical University of Sofia, Rheumatology Center St. Irina (Sofia – Bul- garia).

    Pathologies considered: symptomatic gonarthrosis (Kellgren- Lawrence* Rx grade II-III) without aftereffects of the periar- ticular soft tissues.

    Outcomes

    1. assessment of pain at rest and during movement before and after treatment;
    2. assessment of the Lesquesne Algofunctional Index** be- fore and after treatment;
    3. effectiveness of the MDs used (evaluation by the patient and by the physician).

    Inclusion/exclusion criteria: stated.

    Patients enrolled: 28 (12 M, 16 F, aged 55-70).

    Treatment: MD-Knee, 1 ampoule + MD-Muscle, 1 ampou- le: 2 intra-articular injections/week for 2 consecutive weeks

    + 1 intra-articular injection/week for the next 6 weeks (total: 10 injections in 2 months).

    Results

    Statistically significant reduction of pain (VAS *** = 0-10) at rest (maintained even 30 days after the end of the therapy) and during movement (VAS = 0-10) (maintained even after the end of the therapy) (TABLES. 1, 2). Statistically significant improvement of the indicators of the Lesquesne Algofunctional Index (TABLES 3, 4).

    Authors’ conclusions:

    1. Intra-articular administration of MD-Knee + MD-Muscle in gonarthrosis Kellgren-Lawrence Rx grade II-IIII reduces si- gnificantly pain at rest and during movement and improves the functional activity of patients, who assessed excellent + good in 65% of cases.
    2. The effect persists even after treatment.

    There were no adverse effects in any case.

    ► EFFECTIVENESS OF THE GUNA COLLAGEN MDs INJECTIONS   IN   PATIENTS   WITH  GONARTHROSIS, ANALYSED CLINICALLY AND WITH ECOGRAPHY

    Authors: Nestorova R., Rashkov R., Reshkova V., Kapandjieva N.

    • Clinical Assessment presented at the 9th Central Congress of Rheumatology (CECR 2012) 3rd Annual Meeting of the Polish Rheumatologists – Krakow (Poland) (September 2012), and at the European Congress on Osteoporosis and Osteoarthritis – Bordeaux (F) (March 2012).

    Article published in Rp./Orthopedic 2011/3, Medicine and Sport 2011/4 and PRM 2012; 37-39.

    Experimental sites: Rheumatology Center St. Irina (Sofia); Rheumatology Clinic MBAL “St. Ivan

    Experimental sites: Rheumatology Center St. Irina (Sofia);

    Rheumatology Clinic MBAL “St. Ivan Rilski” (Sofia); Rheu- matology Center MBAL – Rousse (Bulgaria).

    Pathologies considered: symptomatic gonarthrosis (Kellgren-Lawrence* Rx grade III-IV) with aftereffects of the periarti- cular soft tissues.

    Outcomes

    1. assessment of pain at rest and during movement (VAS = 0-10; Lesquesne Algofunctional Index**);
    2. ecographic evaluation before treatment, after 30 days and at the end of the treatment;
    3. evaluation of effectiveness of the MDs used.

    Inclusion / exclusion criteria: stated.

    Patients enrolled: 35 (aged 62-79).

    Treatment: MD-Knee, 1 ampoule + MD-Matrix, 1 ampou- le: peri-articular injections / week for 2 consecutive weeks

    + 1 peri-articular injection /week for 6 more weeks (total: 10 injections in 2 months).

    Results

    1. Statistically significant reduction of pain (VAS*** = 0-10) at rest (maintained even after the end of treatment) and du- ring movement (maintained even 30 days after the end of treatment) (TABB. 5, 6).
    2. Statistically significant improvement of all indicators of the Lequesne Algofunctional Index (examples in TABB. 7, 8).
    3. 60% of patients do not have any edema; 30% achieved a reduction of edema

    – Authors’ conclusions:

    1. ) Intra-articular administration of MD-Knee + MD-Matrix in gonarthrosis Kellgren-Lawrence Rx grade II-IIII reduces si- gnificantly pain at rest and during movement and improves the functional activity of patients.
    2. The effectiveness of treatment was evaluated as excellent

    + good in 68% of patients and 72% of physicians.

    • Periarticular edema improves in 90% of cases as proven by ecography.
    • The effect is maintained even after treatment.

    The analysed MDs have a very high safety profile.

    ►     APPLICATION AND ASSESSMENT OF EFFICACY OF COLLAGEN INJECTIONS GUNA MDs IN GONARTHRO-SIS

    Author: Boshnakov D.

    – Clinical Assessment presented at the XIX Days of Bulga- rian Orthopedics and Traumatology, Tryavna, (September 2012).

    Experimental sites: Saint Anne University Hospital, Varna(Bulgaria).

    Pathologies considered: gonarthrosis.

    Outcomes

    1. assessment of pain at rest and during movement (VAS = 0-10);
    2. assessment of Lequesne Algofunctional Index for:

    a.pain when walking; b.maximum walking distance (in me- ters); c.daily activities;

    3. assessment of efficacy of treatment from the patient’s view- point.

    Inclusion/exclusion criteria: unstated.

    Patients enrolled: 14 (8 M; 6 F; aged 51-72).

    Treatment: MD-Knee, 1 ampoule + MD-Muscle, 1 ampou- le: 2 intra-articular and peri-articular injections/week for 2 consecutive weeks + 1 intra-articular and peri-articular in- jection/week for the following 6 weeks (total: 10 treatments in 2 months).

    Results

    1. Pain at rest: VAS from 2.85 at treatment start (moderate pain) to 0.95 at the end of treatment (no pain) (TAB. 9).
    2. Pain when moving: VAS from 7.3 at treatment start (un- bearable pain) to 3.5 at the end of treatment (moderate/se- vere pain) (TAB. 10).
    3. Lequesne Algofunctional Index: from 1.6 at treatment start to 1.1 at the end of treatment (TAB. 11); maximum walking dis- tance from 100-300 meters before treatment (5.2 score) to 400-700 meters after treatment (3.6 score) (TAB. 12).

    Author’s conclusions:

    1. Intra-articular injections of Collagen MDs improve: a) lo- calized pain; b) pain at movement; c) joint mobility.
    2. Intra- and peri-articular injections improve the patients’ functional activity and quality of life.
    3. The injections of Collagen MDs are a new and effective method to treat gonarthrosis.

    ►     PATELLO-FEMORAL CHONDROPATHY TREATED WITH MD-KNEE + ZEEL® T TRANSMITTED WITH O2 VERSUS

    NIMESULIDE + CHONDROITIN SULPHATE

    Author: Posabella G.

    • Clinical trial presented at the Meeting Sport Medicine, the challenge for Global Health – Rome (September 2012).

    Article published in La Med. Biol., 2011/3; 3-11, and in PRM 2012/1; 3-10.

    Pathologies considered: patella-femoral chondropathy stage I-II-III according to Kellgren-Lawrence.

    Outcomes

    assessment of clinical response (analytical WOMAC****; Le- quesne Index) after administering MD-Knee + Zeel® T trans- mitted with hyperbaric O2 (Group A) versus nimesulide + chondroitin sulphate (Group B).

    Inclusion/exclusion criteria: unstated; randomization.

    Patients enrolled: Group A, 20 [15 M, 5 F; average age 46.4 years (31-66)]; Group B, 20 [15 M, 5 F; average age 46.9 years (28-65)].

    Treatment: Group A – MD-Knee, 1 ampoule + Zeel® T, 1 ampoule, both applied onto the knee skin and transmitted with hyperbaric O2, 1 application/week.

    Group B – nimesulide in 100 mg sachets + Condral (galaco- tosaminoglucuronoglycan sulphate sodium salt) 400 mg, 1/die per os.

    Results

    • After the first week of treatment the patients of both groups (A; B) showed a reduction of the total WOMAC score com- pared to baseline, even if not statistically significant.

    WOMAC Group A = 50 points – Lequesne Index = 17.05 WOMAC Group B = 54 points – Lequesne Index = 17.9

    -Second week

    WOMAC Group A = 47 points WOMAC Group B = 53 points

    -Third week

    WOMAC Group A = 44 points WOMAC Group B = 51 points

    -Sixth week (1st follow-up) WOMAC Group A = 41 points WOMAC Group B  = 50 points

    -Twelfth week (2nd follow-up)

    WOMAC Group A = 39 points – Lequesne Index = 10.4 WOMAC Group B = 47 points – Lequesne Index = 15.3

    Author’s conclusions:

    1. Both Groups of patients (A; B) showed a considerable im- provement of pain and functional limitation.
    2. The data show a more rapid clinical and functional im- provement in the patients of Group A compared to the pa- tients of Group B.
    3. No side effects in the patients of Group A.

    – For comparative analysis of the 4 clinical trials on the osteoarthritis of the knee see TAB.13.

    ►     INTRA-ARTICULAR ADMINISTRATION OF MD-HIP IN 7 PATIENTS AFFECTED BY HIP OSTEOARTHRITIS UNRE-

    SPONSIVE TO VISCOSUPPLEMENTATION.

    -SIX MONTH MULTICENTER TRIAL

    Authors: Migliore A., Massafra U., Bizzi E., Vacca F., Tormenta S.

    – Clinical trial presented at the International Symposium Intra Articular Treatment; Rome (October 2011).

    Experimental sites: UOS (Simple Operating Unit) of Rheu-

    matology – San Pietro Fatebenefratelli Hospital, Rome. Pathologies considered: osteoarthritis X-Ray I-III stage ac- cording to Kellgren-Lawrence affecting the hip joint unre- sponsive to viscosupplementation with hyaluronic acid (6 pa- tients) or hylan (1 patient) (2 ultrasound guided injections at least).

    Outcomes

    1. assessment of efficacy using VAS scale and Lequesne al- gofunctional Index;
    2. NSAIDs consumption before treatment and during follow- up;
    3. safety profile of MD-Hip.

    Patients enrolled: 7

    Treatment: MD-Hip (2 ampoules = 4 ml), 1 ultrasound gui- ded intra-articular injection.

    Results

    1. VAS of osteoarthritis pain = from 6.15 (before treatment) to 4.23 (after 3 months), to 4.23 (after 6 months).
    2. Lequesne Index = from 1.94 (before treatment) to 5.9 (af- ter 3 months), to 5.83 (after 6 months).
    3. NSAIDs consumption = from 7.57 (before treatment) to 4.25 (after 3 months), to 5.78 (after 6 months).

    –  Author’s conclusions:

    1. MD-Hip showed to be effective (all the average values of the results at 3 and at 6 months after the last treatment have been statistically significant) and safe in patients affected by hip osteoarthritis unresponsive to viscosupplementation.
    2. The data suggest that the results can be evident from the very first injection and are stable for 6 months.
    3. The preliminary data offer new research opportunities in the field of intra-articular therapy.

    ►     EFFICACY OF INJECTIONS MD-HIP AND MD-MATRIX IN TREATMENT OF COXARTHROSIS.

    • CLINICAL AND ULTRASONOGRAPHIC EVALUATION

    Author: Tivchev P.

    Article published in Bulgarian Journal of Orthopaedics and Traumatology. Vol 49/2012; 123-8

    Experimental sites: Serdika Hospital (Sofia); Deva Maria Hospital (Bourgas – Bulgaria)

    Pathologies considered: x-Ray stage I-II-III hip osteoarthritis according to Kellgren-Lawrence.

  • THE ROLE OF MD-HIP IN ULTRASOUND-GUIDED INJECTION THERAPY IN OSTEOARTHRITIS OF THE HIP

    ABSTRACT

    Osteoarthritis of the hip is a commonly observed disease in outpatient clinics dedicated to musculoskeletal pain management. The non-surgical therapeutic tools at our disposal are few and not always effective, especially in the advanced stages of the disease, in which joint damage is considerable.

    In recent years, joint injection therapy with hyaluronic acid has become common, using an ultrasound-guided technique to improve the safety and appropriateness of the injection.

    In literature, data on the efficacy of this treatment are more than encouraging. – The combined use of hyaluronic acid and Collagen Medical Device MD-HIP via intra-articular and peri-articular injections are a valuable therapeutic tool in the treatment of hip osteoarthritis.

    Key Words

    COLLAGEN MEDICAL DEVICE, HYALURONIC ACID, MD-HIP, OSTEOARTHRITIS, PAIN, REHABILITATION, INJECTION, ULTRASOUND

    INTRODUCTION

    Osteoarthritis (OA) is the most common arthritic condition and the main cause of disability amongst the elderly population.

    – The hip is the second most commonly affected joint, with a prevalence range between 3% and 11% in the population over 35 years of age.

    OA of the hip is characterised by the progressive de-structuration of the joint cartilage. Clinically, it presents a progressive increase in pain symptoms associated with joint movement, leading to a loss of segmental function and alteration of motor dynamics.

    At the current time, both the pharmacological (NSAIDs, cortisones, low dose medicines and herbal remedies) and non-pharmacological (rehabilitation, physiotherapy, acupuncture) treatment options aim to control pain symptoms, improve the consequent disability and, where possible, restrict the structural damage to the affected joint.

    – Over the past 15 years, intra-articular injection therapy with hyaluronic acid (HA) has become increasingly extensively used worldwide, supported by the good results obtained in certain investigational clinical studies on the reduction of pain and improvement in joint function, making it possible to postpone the need for hip replacement surgery by several years. HA is a high-molecular-weight glycosaminoglycan, constituted by a sequential repetition of glucuronic acid and N-acetylglucosamine. In joints affected by OA, the concentration and molecular weight of physiological HA undergo a 33 – 50% reduction, with an obvious reduction in its effectiveness in protecting the joint. Intra-articular viscoinduction and viscosupplementation are based on HA’s physiological capacity to restore synovial fluid to an optimum viscosity and elasticity and its natural joint-protecting function, overcoming the loss of HA and stimulating its endogenous production, as well as controlling the production and activity of the pro-inflammatory mediators and matrix metalloproteinases. – Guna Collagen Medical Devices (MDs) constitute a significant part of the possible options and therapeutic solutions for

    the treatment of painful and dysfunctional musculoskeletal conditions, such as OA. – With their porcine collagen content and ancillary substances of natural origin (vehicular excipients), they allow a new structuring of the intra-articular tissues (ligaments and joint cartilage) and extra-articular tissues [ligaments, joint capsule, tendons (which are primarily constituted by collagen) and muscles], providing a mechanical scaffold to favour the best arrangement of the damaged collagen fibres and to counter any joint laxity that may cause pain. – In addition, the Guna Collagen MDs improve the viscoelastic properties of the intra-articular fluid, thanks to the cementing function of the collagen fibres of the proteoglycans of the extracellular matrix.

    HA + Guna Collagen MD combination therapy is even more interesting considering the most recent physiopathological hypotheses regarding OA, according to which it is precisely the extra-articular segment, which is far more-richly vascularised, that is the primum movens of the pathological process.

    – The aim of this study was to evaluate the therapeutic efficacy of HA + MD combination therapy in osteoarthritis of the hip.

    PATIENTS AND METHODS

    This clinical study involved patients of both genders (51-77 years of age), who referred to the University Physical Medicine and Rehabilitation Unit – Turin – Italy for hip joint pain. The following inclusion criteria were used:

    • diagnosis of primary OA for more than 12 months, according to American College of Rheumatology criteria;
    • Kellgren-Lawrence radiological classification: grades II-III;
    • moderate-severe pain with Numerical Rating Scale (NRS): score > 5, without taking NSAIDs;
    • walking possible for intermediate distances (> 50 m), without aids.

    Patients satisfying any of the following criteria were excluded from the study: • diagnosis of RA, chondrocalcinosis, psoriasis, metabolic bone disease, gout, active phase infections;

    • OA with rapid impairment, significant or congenital dysplasia of the acetabulum or head of the femur;
    • symptomatic bilateral OA of the hip;
    • previous injections of HA and/or intra- articular or oral cortisone therapy taken in the month prior to inclusion;
    • mental illness;
    • oral anticoagulant therapy, pregnancy, obesity; • orthopaedic or neurological conditions compromising ability to walk.

    Having received specific information on the potential risks of intra-articular therapy and having given their written informed consent – the enrolled patients

    were randomised to one of three Groups (A, B, C). – Group A received a cycle of 3 intraarticular injections of high-molecularweight HA (MW 500-700,000, 20 mg/2mL, Hyalubrix, Fidia Farmaceutici Spa) at 10-day intervals. – Group B received a cycle of 3 intra-articular injections of high-molecular weight HA (MW 500-700,000, 20 mg/2mL, Hyalubrix) and peri-capsular injections of MD-Hip (Guna Spa – Milan) (2 ampoules) at T0, T14 and T35, alternated with 2 peri-/intracapsular injections with MD-Hip (2 ampoules) at T7 and T21. – Group C received a cycle of 2 intraarticular injections of high-molecular weight HA (MW 500- 700,000, 20 mg/2mL, Hyalubrix) and peri-capsular injections of MD-Hip (2 ampoules) at T7 and T14, alternated with 2 peri-/intra-

    capsular injections with MD-Hip (2 ampoules) at T0, T14 and T35.

    The patients included in the 3 Groups were also trained, by means of a short cycle of specific group rehabilitation sessions (Hip School), to correctly perform an exercise protocol to be repeated at home as self-treatment, at least 3 times a week.

    The peri- and intra-articular injection treatment was administered under ultrasound guidance, using a Convex 3.5- MHz transducer with a standard technique (FIG. 1).

    A number of clinical studies published in literature agree on the fact that multiple articular injection treatment does not present a higher risk of adverse events or post-hip replacement infections than single articular injection.

    Clinical and functional outcomes were measured at 3 and 6 months from the first injection treatment.

    The following were quantified:

    1. pain using the NRS;
    2. active range of movement (AROM) of the hip;
    3. functional capacities;
    4. pain using the WOMAC Index (Western Ontario and McMaster Universities Osteoarthritis Index), a multidimensional tool evaluating 17 functional patient activities, in addition to the 5 influenced by pain and the 2 items regarding joint stiffness.

    In addition, any use of NSAIDs by the patients throughout the entire follow-up period and the occurrence of any adverse events was also recorded.

    RESULTS

    The study was conducted on 60 patients who met the inclusion and exclusion criteria and were randomised, stratified by gender and age, in the order of 20 subjects to each treatment Group (Group A, B, and C) (TAB. 2). No patient abandoned the study before the 6-month follow-up. – Pain measured using the NRS had dropped in all 3 treatment Groups at the 3-month visit (T1) and to an even greater extent at 6 months (T2) in Groups B and C

    The active range of movement (AROM) progressively improved on all spatial planes in all 3 Groups (TAB. 4).

    By plotting a graph of the sum of the articular gain obtained by patients in the single Groups at 3 and 6 months, a higher, progressive increase in articular gain is observed for Groups B and C (TAB. 5).

    The WOMAC global score showed an improvement in functional activities for all patients, especially amongst Group B patients at the 6-month visit (TAB. 6).

    By breaking the WOMAC index down into its 3 main items (pain score, stiffness score, function score), the function score increased progressively at both 3 and 6 months in Groups B and C (TAB. 7).

    In the 3 Groups, there was a modest and homogeneous increase in the use of NSAIDs over time (TAB. 8). No adverse events were recorded.

    – All patients included in the study showed good compliance as regards performance at least three times a week of the home exercise programme that they had been taught

    CONCLUSIONS

    The results obtained in this controlled, randomised, clinical study conducted on a homogeneous population with symptomatic osteoarthritis of the hip were those hypothesised during the initial study design phase.

    – HA + MD-Hip combination therapy makes it possible to obtain a more significant and longer-lasting improvement in terms of pain, overall range of movement of the hip and, above all, its function than with treatment with HA alone.

    The use of MD-Hip fills an unmet therapeutic need, making it possible to obtain better clinical results, by acting on the periarticular tissues that play a crucial role in the pathogenesis of osteoarthritic conditions.

    – Moreover, this combination therapy also makes it possible to reduce the number of articular injections of HA, without compromising the therapeutic result, especially with regard to daily activities.

    – As has already been highlighted several times in literature, good compliance in performing a specific home exercise programme with a certain constancy affects the final therapeutic result.

    – During the clinical study, MD-Hip did not show any negative side effect and was seen to have an excellent safety profile.

    Author
    Dr. Edoardo Milano, MD
    – Physical Medicine and Rehabilitation specialist
    S.C. Medicina Fisica e Riabilitazione Universitaria – Torino [University Physical Medicine and Rehabilitation Unit – Turin] Turin A.O. Città della Salute e della Scienza

    Via San Secondo, 37 I – 10128 Turin

  • Collagen

    Collagen is the most abundant protein in man, accounting for 5-6% of adults’ body weight ( Hall, 1964 ). The basic unit of collagen is tropocollagen, a glycoprotein formed by only 4 amino acids (proline, hydroxyproline, glycine, and lysine), organized in a triple helix.

    The triple helix (three alpha-chains) of tropocollagen, the basic unit of mature collagen. The molecule is stabilized by the presence in the alpha chains of hydroxylated amino acids whose H+ bonds give it strength and rigidity.

    This gives the molecule great strength, rigidity, and flexibility. Tropocollagen gives origin to mature collagen, organized in fibrils and then fibers.

    a) Tendon in cross-section [350X magnification (Chèvremont)]. The collagen fibers are grouped in sepimented bundles of different levels.
    b) Hierarchical structure of the tendon according to Kastelic et Al., 1978 (reconstructed and updated).

    Collagen is a real structure-protein, resistant and flexible.

    Collagen fibers play an important role in in the formation of tissues and extracellular matrix, building the scaffold of the body, being the main component of skin, bones, muscles, tendons, ligaments, joint capsules, cartilage, and extracellular matrix.

    Optimal joint functionality is ensured by stabilization structures that are found in:
    1) the extra-articular compartment (ligaments, joint capsule, tendons, and muscles)
    2) the intra-articular compartment (intra-articular ligaments and articular cartilage).

    Extra-articular restraint apparatus. Four reinforcing overlapped structures (1, 2, 3, 4) cooperate to achieve good articular resistance, providing co-axial articular function or articular function according to the physiological slipping axes.

    These structures, which allow stability and locomotion at the same time, consist essentially of collagen.
    Therefore, collagen health is necessary for the health of the entire osteo-arthro-myofascial apparatus.
    Collagen is also essential for activating the repair processes of all tissues; however, collagen turnover is physiologically very slow.

    A – Continuity of collagen fibers in the ligament of adult rats. Electron Microscope images from Provenzano P.P. and Vanderby R. Jr. – Collagen fibril morphology and organization: Implication for force transmission in ligament and tendon. Matrix Biology 25(2006) 71-84.
    B – Post-traumatic repair of the collagen texture. Electron Microscope images from Provenzano P.P., Hurschler C., Vanderby R. Jr. – Connect. Tiss. Res. 42:123-133, 2001.

    Physiologically, the peak of collagen biosynthesis occurs between 45 and 60 years of age. After this age, a quick decrease of collagen is accompanied by a decrease in elastin and proteoglycans as well.

    Life curve of the most important macromolecules of the extracellular matrix (H. – Manuale di Medicina Biologica. Regolazione di base e matrice extracellulare. Guna Editore, 2009.” in Heine, 2009)

    Aging, trauma, posture problems, and chronic inflammatory diseases damage the integrity and the quality of collagen fibers. Collagen fibers appear no longer organized in a parallel or linear way and may display disruptions and overlapping. This prevents collagen structures from acting properly as mechanical support, or scaffold, of the entire body.
    Moreover, a collagen deficiency is always present in inflammatory and/or degenerative diseases of the osteo-arthro-myofascial apparatus and of other structures of mesodermal origin.

    Collagen in arthro-rheumopathies

    Arthro-rheumatic disorders are inflammatory and/or degenerative diseases of the osteo-arthro-myofascial apparatus and of other structures of mesodermal origin such as connective tissue.

    It has been estimated that 15-20% of the general population is affected by pathologies of the Musculo-Skeletal System, better defined as arthro-rheumatic disorders, representing 70% of the patients with chronic pain.
    In modern societies characterized by an increase of factors such as longer life expectancy, overweight, amateur and professional sport activities, unhealthy diet and incorrect use of drugs, the incidence of these pathologies is rapidly increasing, and will increase in future.

    All arthro-rheumatic disorders are characterized by collagen deficiency/ disorders (decrease and degeneration of collagen neo-synthesis).

    After 50 years of age, collagen synthesis decreases dramatically. The weakening of collagen fibers causes laxity in the anatomical structures needed to contain and stabilize the joints. As a result, joint hypermobility, especially in non-physiological directions and angles, causes joint pain and leads to a progressive degeneration of cartilage and tendons.

    Therefore, the primary cause of joint pain is the weakening of collagen structures in the extra articular compartment and in those joints (shoulder, hip, knee) that have intra-articular ligaments. Joint hypermobility, joint overload and misuse increase mechanical stress and cause overuse processes, which are associated to inflammation in the intra-articular and extra-articular compartment.

    The treatment of arthro-rheumatic disorders usually consists of a combination of:

    1) non-pharmacological treatments (e.g. ultrasound therapy, magnetotherapy, laser therapy, tecar therapy, TENS, acupuncture, moxibustion, massages, etc.).

    2) osteopathic and rehabilitative treatments, associated with a change in lifestyle (diet, exercise, etc.).

    3) pharmacological treatments, e.g. COXIB, NSAIDs, paracetamol, corticocosteroids, ASA. However, clinical EBM trials highlight that NSAIDs and COX-2 selective inhibitors are useful only for a short time, against symptomatic inflammatory symptoms and are charged of frequent and even strong negative side effects. In the presence of chronic painful diseases, a prolonged use of these drugs inhibits the healing processes causing lack of mechanical strength and serious articular damage in the medium and long term. NSAIDs reduce the synthesis of new collagen. Moreover, the use of these drugs is contraindicated during treatment with oral anticoagulants.

    4) Viscosupplementation with hyaluronic acid of different molecular weight into large joints (shoulder, hip, knee), aiming at replacing the hyaluronic acid of the synovial fluid, with lubricating and cushioning effect on the intra-articular compartment.

    5) Surgical treatment: prosthesis or fixation (arthrodesis).

    6) Guna Collagen Medical Devices: an innovative therapeutic tool.

    Collagen in Orthopedics, Traumatology, Sport Medicine, Rehabilitative Medicine

    Traumatic injuries, just like overuse and aging, damage the integrity of collagen fibers, which appear no longer organized in a parallel or linear way and may display lacerations.
    This can be the case of acute muscular, ligament or tendon injuries, so frequent in professional and amateur athletes.
    Moreover, continuous micortrauma caused by repetitive stress typical of sports activities also have a detrimental effect of collagen structures.
    The damaged tissue undergoes a long recovery process: a short inflammation phase is followed by a proliferative (repair) phase and then a remodeling phase.
    During the proliferative phase, the fibroblasts are urged to build and reorganize the scaffold of the extracellular matrix, which is mainly composed of collagen.

    During the following remodeling phase, it is important to improve the endurance of the damaged tissue, in order avoid future recurrences.

    Collagen in Aesthetic medicine

    As we age, there is a natural decline in collagen production. There is also an increase in the enzyme collagenase which breaks collagen down.
    This results in an overall decrease in the amount of collagen in the dermis. Another factor contributing to decreased collagen levels is free radicals from UV exposure. Areas with less support begin to cave in and wrinkles begin to form. The destruction of collagen is a major contribution to the loss of skin suppleness and structure that occurs with advancing age.

  • COLLAGEN MEDICAL DEVICE LUMBAR IN THE COMBINED TREATMENT OF LUMBAR INSTABILITYINDUCED PAIN

    SUMMARY

    Spondylolisthesis is a mechanical alteration in the physiological vertebral structure that is primarily characterised by the forward displacement of a part of or whole vertebra on to that below.
    The L-S rachis segment is mostly interested.

    There are 3 kinds of Spondylolisthesis: dysplastic, due to osteo-articular congenital alterations; isthmic, characterized by a continuous lesion of the isthmus; degenerative.

    • The aim of this study is to verify if a combined treatment, Physiokinesitherapy ultrasound-guided injection of Collagen MD (Medical Device)-Lumbar, may provide more important and durable clinical results rather than Physiokinesitherapy alone.
    • 20 patients, F and M, aged between 40 and 75, have been enrolled; all of them suffering from grade 1 and 2 Spondylolisthesis.

    They were randomised to 2 Groups (10 + 10 patients), a treated Group (T) and a control Group (NT).

    The clinical results, evaluated at 2, 4, 8 and 12 months with the Numeric Rating Scale, the Oswestry Disability Index, the Pain Disability Index and the use of NSAIDs (number of tablets/week), allow to state that the combined treatment Physiokinesitherapy + MD-Lumbar obtains a far better and longer-lasting improvement than Physiokinesitherapy alone.

    INTRODUCTION
    Spondylolisthesis (SL) [from the Greek spóndilos (vertebra) and ólístesis (slipping)] is a mechanical alteration in the physiological vertebral structure that is primarily characterised by the forward displacement (anterolisthesis) of a part of or whole vertebra onto that below. Although SL can affect any segment of the spine, it is the lumbar segment that is most commonly affected. Various authors have estimated the incidence of SL in the general population to be 3-8%; however, it can affect up to 20% of the individuals involved in occupational activities or sports requiring hyperlordosis (e.g. artistic gymnastics, gymnastic rings, diving, golf) or in the handling of heavy loads (e.g. weightlifting).

    Clinicians are often called on to identify the origin of spinal pain and equally frequently forget that even a moderate spinal microinstability, such as SL, maybe the cause. One particularly important anatomical point in SL is the vertebral isthmus, the element between the superior and inferior apophyses that forms a connection between the anterior and posterior portion of the vertebra. Undoubtedly, one of the least resistant points of the spine is the lumbosacral junction (L5-S1), where the slope of the upper surface of S1 tends to cause the body of L1 to slip downwards and forwards. This displacement is restricted by the anatomical connections of the posterior arch of L5 and, in particular, by the isthmus.

    SL occurs when the isthmus is subject to interruption or destruction. Furthermore, in addition to the osteoarticular structures, whose focal point are the spinal facet joints, seat to inflammatory processes developed over time driven by the pro-inflammatory cytokine network, the tendinous and ligamentous structures (e.g. the yellow ligament), the capsular structures, the intervertebral disc, the muscle structures (the multifidus muscle and the iliopsoas muscle) and the deep fasciae structures are also involved in the origin of SL-induced pain (mechanical low back pain).


    • There are 3 main types of SL:


    DYSPLASTIC
    The dysplastic form is secondary to congenital osteocartilaginous alterations in the isthmus and consists of 2 main subtypes

    1) the form that is secondary to the sagittal orientation of the articular apophyses of S1 that lose contact with L5, which therefore slips forward;

    2) the form that is secondary to the pathological elongation of the isthmuses of L5.

    ISTHMIC
    In most cases (80%), idiopathic bilateral isthmic lysis involves L5 and it is characterised by a fracture of the isthmus, which causes an increase in the size of the spinal canal, as the posterior portion remains in place
    The inter-articular portion (i.e. isthmus) is the point of least resistance subject to continuous microtraumas that, together with other environmental and genetic factors, reduce its mechanical resilience.

    During development, isthmic SL often occurs following a minor trauma, thus revealing the underlying malformation. The signs and symptoms differ from those observed in adults; young patients experience mild pain without any specific topographical location, even in the presence of significant anterior displacement. In some cases, the only sign is hypertonia of the posterior thigh muscles, making it difficult to flex the limb at the hip with the knee extended.

    DEGENERATIVE
    The degenerative form is very common and is often little considered, partly due to the minimal likelihood of efficacious treatment, which constitutes the target of this study. Unlike isthmic SL, the degenerative form causes a reduction in the dimensions of the spinal canal; the favouring factors are the degeneration of the disc and of the articular apophyses, and an excessively vertical orientation of the articular apophyses.

    In addition to low back pain, it can also be associated with neurogenic claudication caused by spinal canal stenosis. Degenerative SL affects adults; it is caused by long-standing spinal instability and by alterations secondary to the abnormal displacement of the unstable segments, i.e. osteoarthritis and/or degenerative disc disease. This form is 4-6 times more common in females and affects L4 10 times more
    frequently; the anterior displacement can be up as much as 33%.

    The degree of displacement is primarily assessed using the Meyerding Grading System, which classifies it into 4 grades: in grade 1, the displacement is equal to less than 25% of the upper surface of S1; in grade 2 it is less than 50%; in grade 3 it is less than 75%; in grade 4, the entity of the forward displacement can exceptionally reach 100%, with the potential displacement of L5 in the pelvis (Spondyloptosis). The intervertebral disc is inevitably involved; as it is no longer protected by the posterior structures, it absorbs functional overloads that exceed its anatomical characteristics, causing it to undergo a degenerative process that leads to flattening and, eventually, to herniation with an exacerbation of the pain symptoms of SL.

    The nerve components are often involved with the compression of the dural sac and of the nerve roots of L5 and S1. The severity of the SL does not often correlate with the intensity of the pain symptoms.

    The symptoms of SL are 1) mechanical low back pain, which is made worse by movement and improves with rest; 2) irradiation of pain to the lower limbs. Patients often experience a worsening of the pain when changing posture (from sitting to standing). The following symptoms are less common: discogenic low back pain that gets worse when seated and with the forward flexion of the upper body; facet joint pain that gets worse with the hyperextension of the upper body and when standing; neurogenic claudication
    (lower extremity asthenia when walking) caused by the spinal canal stenosis that is often present.

    Anteroposterior, laterolateral and oblique projection x-rays, in addition to a dynamic x-ray study in the position of maximum anterior flexion and maximum extension, are essential for the diagnosis of SL. MRI is used to evaluate the possible compression of the nerve roots and any disc degeneration and/or bulging. It is not always simple to correlate instability (such as moderate degenerative SL) with pain symptoms and it is even more arduous to identify degenerative microinstability at an early stage. The real problem, however, is efficacious conservative treatment. Most patients with SL can be treated conservatively, especially in the presence of the grade 1 and 2 degenerative forms, in which the displacement evolves in approximately 50%of cases, depending on the case histories considered. The conservative treatment of SL is essentially physiotherapy-rehabilitationbased: the aim is not only to strengthen the muscles of the upper body in order to stabilize the spine, but also to improve the neuromotor and proprioceptive control of the pelvic girdle muscles, antigravity muscles and respiratory muscles. It is, of course, essential to re-educate the patient on how to maintain a good static and dynamic posture. In the acute phase, when the clinical situation is characterised by persistent low back pain, it is necessary to observe a suitable period of bed rest, associated with the administration of conventional and/or low-dose anti-inflammatories and muscle-relaxants, either individually or in combination. The optimisation of the conservative treatment of low back pain secondary to degenerative SL, taking into account all the anatomical structures involved in
    this aetiopathogenesis, allows to formulate a number of considerations.

    COLLAGEN MEDICAL DEVICES
    The use of injectable medical devices (MD) containing porcine collagen allows a more efficacious and specific in loco positioning of the collagen, with a carrier and stabilisation function. It makes it possible to replace, strengthen, structure and protect the cartilage, tendons, ligaments and joint capsules, thereby optimising the structure of the collagen fibres and of all the extra- and intra-articular structures in which it is present, thereby providing a mechanical support to the anatomical district in question.

    The hypothesis of the study was that a treatment with a specific injectable Collagen MD could re-condition the anatomical structure/s impaired by SL and improve the stability of the lumbosacral spine; that a “combined” treatment would have been able to improve the functional rehabilitation outcomes and/or provide more efficacious pain control in the subacute and chronic phases; and that a combined treatment would also have been able to positively condition the progression of SL with less frequent exacerbations.

    MATERIALS AND METHODS
    In order to explore this hypothesis, 20 patients with Physical Medicine outpatient clinic appointments for low back pain were recruited and included in the study, from January 2018 to January 2019. The patients were randomised to 2 treatment groups [T Group (Physiokinesis therapy + ultrasound-guided injections of MD-Lumbar) and the NT Group (Physiokinesis therapy alone)], stratified by age and gender; the outcomes were assessed at 2, 4, 8 and 12 months.

    Inclusion Criteria

    F and M patients aged between 40 and 75 years; clinical and instrumental diagnosis of grade 1 and grade 2 Spondylolisthesis; NRS (Numeric Rating Scale) 5, no use of NSAIDs, corticosteroids or opioids.


    Exclusion Criteria

    Rheumatoid arthritis, chondrocalcinosis, psoriasis, metabolic bone diseases, gout, active infections, clinical and instrumental diagnosis of grade 3 and grade 4 spondylolisthesis, spondylolysis, polyneuropathy, previous local/ epidural corticosteroid injections (> 3 years), use of oral corticosteroid and/or opioid therapy in the past 6 months, use of anticoagulants, pregnancy, mental diseases.


    Both the T and the NT Groups were administered the same intra-hospital rehabilitation protocol (diagnostic and therapeutic care programme) based on neuromotor treatment for the proprioceptive reconditioning of the posterior back, lumbosacral girdle and respiratory muscles.

    The protocol also included ergonomic education and occupational therapy. The rehabilitation treatment consisted in: daily individual motor rehabilitation treatment for a total of ten 45-minute sessions; individual assessment by the occupational therapist at the 5th and 10th session; provision of a brochure illustrating the physiokinesis therapy exercises to be performed by patients at home and ergonomic advices; group treatment (max. 4 patients) one month after the last individual session, on 2 consecutive days, in 30-minute sessions.

    • Group T (Treatment) also received ultrasound-guided injection therapy (Clarius Ultrasound portable system, Convex probe) according to the following protocol:

    GUNA MD LUMBAR Pack of 10 Ampoules of 2ml – Urenus

    5 sessions (1/week for 4 consecutive weeks and 1 after 15 days); 2 vials of MD-Lumbar per treatment. − Half a vial (1 mL) for each facet joint; 2 joints were treated at each treatment, alternating the upper and lower facet joints; at the 5th session the 2 most impaired joints (as shown by MRI) were treated.

    A number of clinical and functional outcomes were investigated:
    1) Numeric Rating Scale (NRS)
    2) Oswestry Disability Index (ODI)
    3) Pain Disability Index (PDI)
    4) use of NSAIDs during the follow-up period (TABLES 1, 2 ,3 and 4).

    CONCLUSIONS
    The data obtained (TAB. 5) allow to conclude that in the treatment of grade 1 and grade 2 Spondylolisthesis combined treatment with physiokinesis therapy + injection of MD-Lumbar makes it possible to obtain a far better and longerlasting improvement, in terms of

    1. pain
    2. motor function
    3. impairment caused by spinal instability
    4. reduced use of NSAIDs.

    Furthermore, the combined treatment proposed herein, for the first time in the treatment of Spondylolisthesis, would appear to allow a better control over disease progression and a reduction in exacerbations over time (pro-inflammatory cytokine network control).

    From the data obtained, it emerges that:
    − NRS. Group T (Physiokinesis therapy + ultrasound-guided injection therapy of MD-Lumbar) passes from 6.9 (T0) to 2.5 after 12 months (-63.8%).
    Group NT (Physiokinesis therapy alone) passes from 7.1 (T0) to 5.7 after 12 months (-19.7%).
    − ODI. Group T passes from 41.0 (T0) to 14.0 after 12 months (-65.9%). Group NT passes from 42.0 (T0) to 34.0 after 12 months (-19.1%).
    − PDI. Group T passes from 64.0 (T0) to 38.0 after 12 months (-40.6%). Group NT passes from 62.0 (T0) to 64.0 after 12 months (±0%).
    − NSAIDs (tablets/week). Group T passes from 1.3 at 2 months to 1.4 at 12 months (±0%). Group NT passes from 2.0 at 2 months to 3.0 at 12
    months (+50%).

    MD-Lumbar improves the stability of the lumbosacral spine and organically reconditions the impaired anatomical structures (joint capsules, yellow ligament, antigravity muscles and connective deep fascia), thereby making a considerable contribution to the promotion of neuromotor and proprioceptive capacity.

    Over the next few months, we hope to be able to confirm the results obtained by expanding the study sample and, in particular, to identify the optimum timing for further injection therapy with MD-Lumbar as part of an individual maintenance rehabilitation programme.

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    Fig. p. 40
    https://urbanministries.com/wp-content/uploads/2019/01/iStock-927091262-Pain.jpg

    Fig. p. 41

    Left:
    https://eorthopod.com/images/ContentImages/spine/spine_lumbar/lumbar_spondylolistheis/lumbar_spondylolisthesis_cause02.jpg
    Right:
    https://www.brainspinesurgery.com/uploads/img/_800xAUTO_crop_center-center_60/Spondylolisthesis-Spine-Condition-and-Symptoms-Xrayy.png

  • Low Dose Cytokines

    GUNA – ANTI IL 1
    INGREDIENTS: Anti-interleukin 1 alpha 4CH; Anti-interleukin 1 beta 4CH.
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Regulates the immune response in inflammatory
    conditions.
    USES:
    • acute pain and fever relief
    • inflammation
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERFERON ALFA
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Antiviral activity.
    USES:
    • recurrent viral infection
    • joint pain
    • asthenia
    • sudden pain with numbness
    • painful muscle spasm
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERFERON GAMMA
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Antiviral activity. NK cell activation. Macrophage
    activation. Anti-proliferative effects. Enhancing the activity of T lymphocytes.
    USES: Rapid activation of the immune system(activation of the antigen
    presentation). Stimulation of antiviral defenses. Treatment of autoimmune
    diseases with risk of viral super-infection. Treatment of hepatitis C and B.
    • chronic viral infection
    • allergic syndrome
    • complementary cancer therapy
    • asthenia
    • painful muscle spasm
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 1 BETA
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Fever induction, as alert against attack (endogenous pyrogen).
    USES: Acute immune attack. During the first hours of fever on a viral basis.
    • asthenia
    • sleep disorders
    • eating disorders (excessive hunger)
    It must be used intermittently, for a time necessary to induce fever.
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 2
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: T lymphocyte differentiation. B lymphocyte and NK cell stimulation.
    USES: Regulation of cell-mediated immune response.
    • immune deficiency
    • general malaise
    • sub-acute painful syndromes
    • localized inflammation
    • aging
    • complementary cancer therapy
    • prostration, adynamia
    • burning mouth
    • susceptibility to viral infections
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 3
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Stimulation of mast cell growth. Stimulation of hematopoiesis.
    USES: Treatment of hematopoiesis disorders.
    Treatment of the side effects due to chemotherapy, radiotherapy and of treatment with allopathic antiviral
    drugs.
    • hemopoiesis disorders
    • side effects due to chemotherapy, radiotherapy and antiviral treatments
    • early aging
    • memory impairment
    • digestive disorders
    • dizziness with vomiting
    • skin rashes
    • migrating pain
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 4
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: B lymphocyte proliferation. IgG and IgE synthesis. Inhibition of proinflammatory
    cytokines.
    USES: Modulation of inflammation.
    It improves the individual response to vaccine therapy.
    • basic treatment of autoimmune diseases
    • chronic inflammatory diseases
    • cramps and spasm
    • mental exhaustion
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 5
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Eosinophil and basophil differentiation, growth and maturation.
    USES:
    • intestinal parasites
    • pain caused by contusion
    • constipation and tympanites
    • abdominal pain (cramps)
    • RRI with IgA deficit
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 6
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: B lymphocyte growth and differentiation. Co-stimulation of T lymphocyte.
    Hepatic stimulation. Endocrine factor of the cytokine Network.
    USES: Complications in the clinical evolution of a patient affected by autoimmune disease.
    Stimulation of general immunity in cancer patients.
    • general malaise
    • complementary cancer therapy
    • eating disorders (excessive hunger)
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 7
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Thymocyte and T lymphocyte proliferation.
    USES:
    • recurrent infections
    • asthenia
    • disorders of childhood growth and development
    • throbbing pain
    • exhaustion and fatigue
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 8
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Phagocyte, T lymphocyte and platelet chemotaxis.
    USES:
    • chemotaxis activation
    • wet cough
    • phlegm
    • acute and chronic stress
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 9
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Lymphocyte stimulation. Synergism with Erythropoietin
    in the development of erythroid proliferation.
    USES: Induction of specific immune response.
    • asthenia and drowsiness
    • nerve pain
    • chronic phlegm
    • water retention
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 10
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Immunosuppressive and inhibiting action on the cytokine Network.Modulation
    of physiological reactivity.
    USES: Modulation of the immune tolerance mechanisms. Modulation of inflammation.
    • chronic inflammatory diseases
    • itch and sting
    • mucosal inflammation
    • chronic pain syndromes
    • vomiting-loss of appetite
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 11
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: Regulation of the growth and the differentiation of hematopoietic cells. Control
    of the proliferation of other interleukins.
    USES: Induction of specific immune response.
    • heartburn
    • memory disorders
    • hematopoiesis disorders
    • psoriasis
    • abdominal bloating
    • general regulation in patients under immunotherapy
    • disorders of childhood growth and development
    • throbbing pain
    • exhaustion and fatigue
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.

    GUNA -INTERLEUKIN 12
    DILUTION: 4CH
    BIOLOGICAL FUNCTIONS: NK cell and T lymphocyte stimulation.
    USES: Regulation of cell-mediated immune response. Complementary treatment of allergy.
    • allergy
    • food intolerance
    • complementary cancer therapy
    • recurrent night-time cough
    • nasal congestion and nasal itching
    • paroxysmal sneezing
    • watery eyes due to allergy
    • skin swelling and skin inflammation
    DIRECTIONS: 15-20 drops two times a day (standard dosage).
    PACKAGE SIZE: 30 ml/1.0 fl. Oz. bottle with dropper. For oral use.